1. Field of the Invention
Low frequency electromagnetic radiation and radio frequency electromagnetic radiation are applied separately or in combination with one another to a target area of a patient. The electromagnetic radiation alters the control system of at least some of the cells forcing them to return to a normal cellular control system, and/or the electromagnetic radiation serves to promote apoptosis or cell death in at least some of the cells, with little to no effect on the surrounding normal cell population.
2. Description of the Related Art
Cells contain mechanisms that regulate and control their various activities, among these are the control mechanisms that maintain proper growth rates of a cell, as well as the timing of cell death, when appropriate. Normal cells grow or replicate in response to an external signal, such as a growth factor that acts on an extracellular membrane bound protein, initiating a signaling cascade that ultimately leads to cell growth. For example, nerve growth factor, platelet derived growth factor, and epidermal growth factor, represent three such factors. Thus, growth in a normal cell is externally regulated and includes an important external input.
Normal cells also include mechanisms which control programmed cell death, or apoptosis. It is important that cells die off in order to limit the number of genetic mutations in a population of cells, which occur more frequently with increased cell divisions, as well as to keep tissues and organs functioning properly.
A number of factors contribute to the control and orchestration of cell growth, as well as cell death. Perhaps the most basic of these is deoxyribonucleic acid (“DNA”). DNA is a complex biomolecule comprised of a series of corresponding base pairs of nucleic acids. These base pairs may have positive or negative charges, which therefore render positive or negative charges at various points along the DNA molecule. Due in part to the charge distribution, DNA can assume a number of shapes or conformations depending on the quantity and movement of charge in the biomolecule. For instance, DNA can be in a linear conformation with a negative charge in its base pairs, thereby forming double helix as is the case with nuclear DNA. It can also be in a circular form, such as in mitochondrial or bacterial DNA. Thus, DNA comprises the building blocks from which cells are formed.
Moreover, DNA contains the genetic information of the cell, and must be copied or replicated each time the cell divides. Similarly, DNA strands must be separated and sorted into dividing cells during mitosis, i.e., growth, and meiosis, i.e., reproduction, in order to convey the genetic information to the next generation of cells. Therefore, these processes also affect the rate of cell growth, and the conformation of the DNA molecule affects the replication, mitosis, and meiosis processes.
Microtubules also affect cell growth. A microtubule is a hollow cylindrical polymer dipole with its negative pole at the centrosome of the nucleus of a cell and its positive pole at the cell membrane. Microtubule growth occurs at the positive pole at the cell membrane, and therefore can be said to radiate out from the centrosome. Accordingly, microtubules connect the cellular membrane to the nucleus of a cell. Microtubules are also used within the nucleus to guide separating DNA strands during mitosis.
Energy drives the many processes in a cell, including growth, DNA replication, mitosis, and meiosis. The cell is a self-regulating system where the functions are regulated within the energy level required. More in particular, the cellular control system sets the level of energy required for a specific function of the cell. This energy, in the form of adenosine triphosphate, or ATP, is synthesized in the mitochondria of the cell.
A proton driven ATP synthesis is a critical mechanism of the cellular control system. Specifically, the electron transport chain is a series of proteins associated with the mitochondrial membrane that transfer electrons stepwise between the proteins. Simultaneously, protons are pumped against an electrochemical gradient to the exterior of the membrane. Energy is temporarily stored in this proton gradient. Upon flowing back through the inner membrane, these protons are acted upon by the membrane bound enzyme ATP synthase to relinquish this energy to ATP, an energy storage mechanism which stores this energy in phosphate bonds.
The protein cytochrome C is an important component of the electron transport chain located in the inner mitochondrial membrane. Rather than being membrane bound, cytochrome C is loosely associated with the inner membrane by covalent bonds and flows along the inner membrane. Furthermore, cytochrome C has a heme group containing iron that allows cytochrome C to transport electrons between proteins. It is a central component of the electron transport chain and ATP synthesis.
Significant energy is produced through ATP synthesis mediated by the electron transport chain. For instance, the protons pumped across the membrane exert an electrochemical gradient reaching about 60 to 100 milliVolts (“mV”). This is in addition to the normal potential across the membrane of about 140 mV. Accordingly, at its maximum, the total potential is in a range of about 200 to 240 mV. Moreover, with a low proton gradient, electron transport occurs at a maximum rate, while an increase of the proton gradient causes a decrease in electron transport. Thus the magnitude of the electrochemical gradient can affect both the rate and direction of the electron transport, in turn determining the amount of ATP generated.
Cellular energy production does not change gradually or continuously, but jumps between different levels, wherein different levels of energy are required to perform different cellular functions. For instance, the electron transport chain can operate to produce energy at a basic level, such as to maintain resting membrane potentials, etc., or jump to a new level as required for meiosis and cell division, etc., or jump to a functional level for secretion, contraction, etc. Once the energy is produced, it is stored in the phosphate bonds of ATP.
The discharge of energy from ATP can be accomplished by hydrolyzing the energy rich phosphate bonds. A first hydrolysis step reduces ATP to adenosine diphosphate, or ADP. A subsequent step reduces ADP to adenosine monophosphate, or AMP. A further step reduces AMP to pyrophosphate. Each of these steps hydrolyzes one phosphate bond, releasing significant energy to be utilized by the cell in various ways, such as to maintain membrane potential, enzymatic activity, protein synthesis, mitosis, etc. Corresponding with each hydrolysis step is a decrease of the electric charge of the molecule as ATP has a negative electric charge of four; ADP, three; AMP, two; pyrophosphate, one.
Proteins also affect the rate of cell growth and death. For instance, proteins are critical to a variety of cellular processes, including ATP synthesis, signal transduction, cell division, secretion, etc. Proteins are comprised of a series of amino acids and assume three dimensional conformational shapes. Moreover, proteins may have positive or negative charges appearing at various points in the molecule, often in relation to amino- or carboxyl-groups or charged side chains. For example, in the circular form of a molecule, there may be a negative charge at one pole and two positive charges at the other pole, the charges themselves, being attractive, contribute to a circular form of the molecule. For instance, the amino acids glutamine and arginine, at each pole, can assume this charge of positive and negative.
Complex proteins can assume any of at least three (3) energy states, namely, from lowest to highest: linear; circular; or twisted. A possible intermediate horseshoe form exists between linear and circular in energy. As a result of charge differential over the molecule, membrane proteins are dipoles which can turn and twist under electric field changes to the membrane potential. These molecules can be linear or circular, horseshoe or twisted in their conformation, each having a corresponding electrochemical state. Depolarization of the membrane can change the conformation of the protein to an active state, such as from a linear to a circular conformation. Associated with the twisted form of the protein is a distribution of negative and positive charges along the molecule which represents the highest energy state of the molecule, and thus, when the molecule changes conformation into the circular form, a significant amount of energy is released.
Conformational changes of membrane bound proteins can be affected by the membrane potential, as is evidenced in the example of the Na+/K+ voltage gated ion channel. Specifically, there is a net amount of potassium ion (K+) inside the cellular membrane and a net amount of sodium ion (Na+) outside, wherein the membrane is permeable to potassium ion (K+), but is impermeable to sodium ion (Na+). In nerve and muscle cells, when the membrane is depolarized upon the application of electric current, the voltage gated ion channel is activated, initiating an action potential across the membrane and inducing a conformational change in the voltage gated ion channel, which in turn allows sodium ion (Na+) to enter the cell. The subsequent flow of potassium ion (K+) across the membrane repolarizes the membrane, to a potential in the range of approximately 50 to 100 mV.
There are many types of membranes within a cell, each having a membrane potential. The membranes include the cellular outer membrane, the mitochondrial inner and outer membranes, and the nuclear membrane. The cellular membrane can be described as a lipid bilayer with a mosaic of protein impregnations or imprints. Here, the membrane potential is established by a negative charge on a protein whose hydrophilic end projects into the interior of the cell. This potential determines the movement of ions and molecules across the membrane, such as discussed above for potassium ions (K+) and sodium ions (Na+). However, it is also possible that protons (H+) also move across the membrane, as a consequence of electron transport as described above in relation to ATP synthesis at the mitochondrial membrane. The membrane of the mitochondria involves the control of metabolism, mainly oxidative, by its potential, and ATP synthesis via electron-proton transport. The nuclear membrane, in the interior of the cell, contains the DNA of the cell within its boundary.
The lipid bilayer of a cellular membrane is interspersed with proteins of various composition and function which are charged, such that they have a dipole moment. Although all cells have a membrane potential or dipole moment, studies on membrane potential have been essentially limited to muscle or nerve cells where changes in the membrane potential are the result of an electrical signal. In muscle cells, this electrical signal initiates contraction of the muscle. In nerve cells, this electrical signal initiates the transmission of neurotransmitters between neurons.
Although all cells exhibit electrical properties, this has been investigated seriously only in nerve, brain and muscle cells, and the action potential is the predominant observation. All cells have a membrane potential, but only nerve and muscle cells are able to produce an action potential which is both a signaling and activating mechanism. The action potential normally is initiated at one end of a nerve or muscle cell by a depolarization of the membrane, resulting in a reduction of the magnitude of the potential. At a certain point of depolarization, called threshold, the action potential is discharged and is self-propagated to the other end of the cell to end in a synapse or junction, where it generates a depolarization called a synaptic potential. The depolarization causes the release of a neurotransmitter which diffuses across the synaptic gap to depolarize the postsynaptic cell body (which contains the nucleus, mitochondria, ribosomes, etc.), to produce an action potential in the postsynaptic cell which can repeat this process.
The nerve cell, or neuron, may be either excitatory or inhibitory. The excitatory neuron acts as previously described to produce a depolarization. On the other hand, the inhibitory neuron releases an inhibitory neurotransmitter which acts to hyperpolarize the postsynaptic cell body, creating an increase in the magnitude of the membrane potential and can prevent activity or an action potential in the postsynaptic cell.
Changes in the cellular membrane potential of a postsynaptic cell can cause a change in the genetic material within the nucleus of that cell. For example, the action potential impacting the cell body of a neuron, or nerve cell, produces a depolarization which activates the FOS gene which is related to growth and regulation. FOS is also a known proto-oncogene, meaning that an appropriate virus can transform it into an oncogene, thereby initiating a cancerous process.
There are relevant functions which membrane polarization regulates. For instance, in the neuronal membrane, polarization results in the switching on of the action potential, also referred to as depolarization of the membrane to threshold. The membrane acts as a semiconductor where current can be turned on or off, wherein the transport system or other function can be turned off by hyperpolarization of the membrane.
Although the membrane potential is a Donnan or electrochemical equilibrium potential, it requires an appreciable amount of energy to maintain it. To maintain the membrane potentials, mitochondrial energy production is needed to synthesize ATP, which is used as the energy source separating ions across the membrane and maintaining the membrane potential. For example, the inner membrane of the mitochondria maintains a membrane potential of about 140 mV as a result of the Na+/K+ voltage gated ion channel. However, the membrane potential can increase anywhere from about 60 to 150 mV due to the accumulation of protons on the cytoplasmic side of the membrane, for a total potential in the range of about 200 to 290 mV. Accordingly, a significant amount of energy is required by the cell to maintain membrane potentials, as well as cellular processes within the cell that keep the cell functioning normally.
Unlike normal cells, abnormal cells do not possess the normal cellular control mechanisms and instead exhibit, among other things, uncontrolled cell growth and immortality. For instance, abnormal cells may have genetic mutations, such as gene deletions, additions, point mutations, etc., that result in the interference of normal cell functioning and processes. This is the case in cancer cells, as well as cells infected with a virus such as H1N1 influenza, more commonly referred to as swine flu, or human immunodeficiency virus (“HIV”). Moreover, cancer cells and virally infected cells share some of the same fundamental components and mechanisms.
One of the features common to abnormal cells such as cancer cells and virally infected cells is an uncontrolled growth rate. For instance, the cancer cell appears to have an almost constant signal to grow and reproduce. Specifically, growth or reproduction of the cancer cell is a result of a signal to grow and reproduce that is internally generated by the cancer cell. In other words, the cancer cell can grow in the absence of outside or external signals. This is in stark contrast to normal cells which grow and divide only in response to an external signal such as a growth factor. Accordingly, growth of cancer cells is entirely internally regulated and independent of the limitations of its environment, and therefore can grow continuously. Indeed, this uncontrolled growth is a major factor contributing to the production of tumors in cancer tissue.
A cancer cell's development can be broken into two phases, wherein the cancer cell behaves differently in each phase. The first phase is called initiation or promotion, and occurs when the cancer cell is first initiating and developing. This phase is generally accepted to be reversible. The remaining phase of the cancer cell's development is called progression and is considered to be irreversible. During this phase, the cancer cell propagates and proliferates, and can lead to the growth of tumors, invasion of neighboring tissues, and even metastasis to distant parts of the body. In order for the cancer cell to metastasize, it must break away from its adhesion to adjacent cells or the extracellular matrix and enter the blood or lymph stream. Then the cancer cell eventually adheres to another tissue, organ, or cellular structure.
In a number of aspects, including growth, an infected cell acts similarly to a cancer cell, except that the progeny are viruses rather than cells. Once inside a host cell, viral DNA is integrated into the host cell DNA through a process called transgenesis. Depending on the point of insertion, transgenesis may inactivate a tumor suppressor gene which repairs damage, and therefore, renders the cell incapable of repairing damage. This can lead to increased incidence of genetic mutations and, ultimately, cancer in the cell. A similar result may occur from infection by an oncogenic virus, which induces cancerous type growth in the cell. Regardless of the method of transgenesis, once integration of viral DNA into the host genome is complete, the virus induces the host cell to continuously replicate, thereby also replicating the viral DNA. This replication occurs until the cell bursts, releasing a multitude of virus molecules into the body. Indeed, this is the goal of the virus, allowing its genes to propagate throughout a host organism. Importantly, the signal to replicate comes from the virus itself, and therefore, similar to a cancer cell, it is internally controlled. Since it does not rely on external factors for growth, the virally infected cell can continue to grow continuously until the cell bursts. Thus, the cancer or infected cell supersedes the control system of the normal cell regarding growth.
Apoptosis, or programmed cell death, is also a part of a normal cell's control system. Abnormal cells, such as the cancer cell and virally infected cell, no longer have a signal to initiate apoptosis and, therefore, these cells do not die off, rather, they become immortal.
Cellular structures and molecules are known to exhibit electrical and magnetic properties. For example, as previously discussed, molecules such as proteins and DNA can have charged regions or components, whether positive or negative, which contribute to the electrical activity of the molecule. Membranes also have electrical properties as a result of the electrochemical potential established and maintained by the presence and movement of ions around and across the membrane. As mentioned previously, most of the information concerning electrodynamics of the normal cell has been obtained from studies of nerve and muscle cells.
Cellular structures and molecules also exhibit magnetic properties. For instance, the protons within nuclei of cells are responsive to a magnetic field. Since each proton is a dipole, it will align or spin in a particular direction, either up or down, when placed in a magnetic field. Placing a cellular sample in a steady state magnetic field results in the orientation of the protons of the cellular sample so they spin in the same direction, i.e., all up or all down. Application of a magnetic pulse, 90° out of phase, excites the protons of the nuclei and forces the protons into the transverse plane. Subsequent to the application of the magnetic pulse, the protons return to their original position generated by the steady magnetic field, known as relaxation. This relaxation has a characteristic time constant, or duration of excitation, unique to each cellular sample type. For instance, the time constant is different for different types of tissues of the body, and the time constant for cancer tissue is different than for non-cancerous tissue of the same type. Fluids have a relatively long time constant, in the range of about 1,500 to 2,000 milliseconds (“ms”), whereas water containing tissues have a time constant of about 400 to 1,200 ms, and fatty tissues have a shorter time constant in the range of about 100 to 500 ms.
Thus, protons in different tissues of the body have different periods of excitation duration, or time constants. An example of this is presented in Table 1 below showing the excitation times of proton populations for each of two different magnetic flux densities, 0.5 Tesla (“T”) and 1.5 T:
TABLE 1Proton Population0.5 T1.5 TSpleen760 ms1,025 msLiver395 ms570 msFat192 ms200 msMuscle560 ms1,075 msCSF—2,060 msGrey Matter (Brain)780 ms1,100msWhite Matter (Brain)520 ms560 ms
Moreover, the Larmor frequency (r/2πB), which relates to the angular momentum of a spinning or precessing proton, for excitation of a proton (H+) increases with an increase of the magnetic field, or magnetic flux density. For example, at 0.15 T it may be 6.39 MHz; at 0.5 T, 21.29 MHz; at 1.5 T, 63.87 MHz; at 3.0 T, 127.74 MHz.
To date, the utilization of the electrical and magnetic properties of cellular components and molecules to affect changes in a cell have been essentially limited to cardiac pacemakers or defibrillators, the magnetic stimulators, and the magnetic resonance imaging (MRI).
The cardiac pacemaker is used therapeutically to deliver an electrical current or voltage directly to the heart muscle cells, usually those in the ventricle, in order to correct fibrillation or tachycardia. Specifically, the rate at which the heart pumps blood is controlled by the medulla in the brain which sends signals via sympathetic and parasympathetic nerves to the SA node of the heart to modulate the nodes' oscillatory depolarizations, thus producing the heart rate. If the heart rate becomes too high, as in the case of tachycardia, fibrillation may result, which is characterized by groups of ventricular muscles contracting independently of the SA node and each other, or asynchronously, resulting in a negligible blood pressure. The defibrillator corrects this by temporarily stopping the heart with an intense electric shock, after which, the heart should return to its normal rhythm. The pacemaker therefore utilizes the electrical properties of cells and neuronal signaling to effect a change in the body.
The magnetic stimulator, such as manufactured by MagStim and Danntec, has been used for diagnostic purposes, rehabilitation and psychological research. Essentially, the magnetic stimulator delivers current or voltage to nerve cells, either in the brain or peripherally, via a magnetic field to depolarize motor cortex neurons and measure nerve conduction time. This involves the use of magnetic coils placed over a target area to produce a pulsed magnetic field, thereby inducing an electric field and resulting in an electrical current applied to a targeted area of the brain. Despite the use of a magnetic field to generate an electrical current, the magnetic field is not directly utilized for therapeutic purposes.
Magnetic resonance imaging (“MRI”) utilizes an EMR field applied to selected regions of the body for the purpose of producing an image. To accomplish this, magnetic fields are applied to specific regions of the body in order to excite particular cellular components, such as protons within molecules or nuclei of cells. The excited protons or nuclei then release this excess energy and return to equilibrium levels via the process of relaxation, and the time required for this return to equilibrium is known as the relaxation time. Raymond Damadian discovered in the early 1970's that the relaxation time of cancer cells is different from the neighboring normal cells, and thus the presence of cancer can be determined and its magnitude observed. Accordingly, MRI utilizes the EMR properties of cells to provide an image of the tissue or organ, however, it does so based upon the magnetic properties of cells, without utilization of the electrical currents induced by the MRI equipment itself.
Despite the fact that medical technology has utilized both electrical and magnetic properties of cells, cellular components and molecules independent of one another, no known medical technology simultaneously controls and utilizes both electrical and magnetic properties for therapeutic treatment purposes.
The interrelation between electric and magnetic properties of cells may be observed. For example, when tissues or organs or body parts are exposed to a changing magnetic field, an electric field is produced which causes a current based on ionic movement. Positive and negative ions move in opposite directions, similar to the interior of an electric battery. Accordingly, there is energy imparted by the magnetic field. For example, according to quantum mechanics, there are only two possible states of a proton (H+), with values of ±½, corresponding to whether the proton is in the spin up or spin down direction. The energy (E) of each state is:E=μB=rhI·B where B is the magnetic field, h is Planck's constant, μ is the angular momentum, r is the gyromagnetic ratio, and I is the Angular momentum quantum value (½ for protons).
Present treatment regimens for cancer patients include surgery, chemoradiation, and pharmaceutical drugs, which are directed primarily to the removal or eradication of the cancer cell population. However, these methods cannot be limited solely to the cancer cell population, and as a result, normal healthy cells are also removed and/or eradicated in the process.
For example, surgery has been a common technique for combating cancer, and is often used for the removal or excision of tumors. However, there are significant risks involved with surgical treatment, as with any surgery, including possible complications, hemorrhaging, adverse reactions to aesthesia, etc. Moreover, surgical removal of cancer cells is only feasible once the cancer has grown to a substantial population, and can therefore not be implemented for precancerous or early stages. While precancerous cells exhibiting abnormal characteristics can be surgically removed in order to avoid the development of cancer, this often involves removal of surrounding normal healthy tissue as well. Further, surgery may not be practical for the treatment of other forms of abnormal cells, such as those infected with a virus.
Chemoradiation has also been used to treat cancer. The main problem with this therapy is safety. Chemoradiation involves subjecting tissue to toxic levels of radiation, which is intended to damage the DNA of the cells within the irradiated tissue, and thereby prompt cell death. However, this is a highly risky procedure as it is difficult to isolate just the cancer cells, and so the surrounding healthy tissue cells are also irradiated, damaged, and die. Because of its safety problems and lack of specificity, chemoradiation can only be utilized a limited number of times. Moreover, the cancer cell can mutate to become resistant to chemoradiation, further complicating treatment. Similar problems would be encountered if chemotherapy or chemoradiation were used to treat other abnormal cells, such as virally infected cells.
Cancer research, and in particular, research guided by the National Institute of Health, has been aggressively pursuing pharmaceutical treatment regimens since the discovery of the first significant anticancer drug, cis-platinum over fifty years ago. However, the results have not been particularly significant given the effort and funding levels directed to this research. For example, although a number of new anticancer drugs have been developed by pharmaceutical companies, they have not succeeded in significantly increasing present levels of effectiveness which, with few exceptions, have improved only minimally over the past fifty years. Also, most if not all pharmaceuticals for treating cancer produce significant adverse side effects. This is also the case for many of the antiviral drugs on the market. Thus, it appears critical to develop a new treatment regimen that could complement, if not replace altogether, present treatment regimens. It would be significantly beneficial for such a new treatment regimen to comprise none of the harsh and often detrimental side effects of known treatment regimens.
It is evident that known treatment regimens for cancer cells are non-specific, and equally and adversely impact all cells, normal and abnormal, in an affected area. More in particular, the known treatment regimens involving chemoradiation and/or pharmaceuticals are highly toxic to all cells and produce significant adverse side effects, and known treatment regimens requiring surgery involve removal of healthy cells along with target cancer cells. In any case, the known treatment regimens for cancer cells are simply not completely effective. Accordingly, the medical community needs a safe and effective treatment regimen for cancer cells.